Deciphering DST -associated disorders: biallelic variants affecting DST-b cause a congenital myopathy

Brain, vol. 149, pp. 653–667

Abstract

The dystonin gene (DST) encodes three major isoforms, DST-a, DST-b and DST-e. Biallelic pathogenic variants in DST have previously been associated with two allelic monogenic disorders: hereditary sensory and autonomic neuropathy type VI (caused by a loss of DST-a) and epidermolysis bullosa simplex 3 (caused by a loss of DST-e). We investigated patients diagnosed with congenital myopathy using exome or genome sequencing. In 19 affected individuals from 14 unrelated families, we identified nine different variants in biallelic state located in exons 40-41, specific to DST-b. Affected individuals presented with severe neonatal myopathy characterized by arthrogryposis, hypotonia and dilated cardiomyopathy. Postnatal CPAP ventilation was required in nine patients, and seven died within the first three years of life. Survivors showed an improvement of symptoms, with the oldest three patients, now over 25 years old, exhibiting normal cognition and being ambulatory. RNA analyses demonstrated that transcripts encoding DST-b are predominantly expressed in skeletal muscle, heart tissue and cultured fibroblasts, but not in brain, matching the phenotypic spectrum. Patient-derived fibroblasts exhibited reduced DST mRNA expression. Proteomic analysis confirmed a reduction of DST protein levels due to an absence of the DST-b isoform. Muscle biopsies from four patients aged 1 month to 3 years revealed mild, non-specific myopathic changes. Ultrastructural analysis in three individuals showed mild and focal myofibrillar disruption and non-specific undulating nuclear membranes, with these changes observed in two cases each. Additionally, we identified two homozygous variants affecting both DST-a and DST-b isoforms in four patients from two unrelated families; all presented with severe arthrogryposis and died intrauterine or shortly after birth. Genotype-phenotype correlation in these patients and previously published cases with respective variants resulted in the definition of a DST-associated lethal congenital contracture syndrome. Our findings demonstrate that biallelic variants exclusively affecting DST-b cause an autosomal recessive congenital myopathy. Variants that also impact DST-a besides DST-b result in a more severe, lethal congenital contracture syndrome. The location of the variant within DST allows for phenotype prediction. We propose redefining DST as a disease-associated gene linked to four distinct allelic disease phenotypes.

Authors 51

1. Maureen Jacob

   Institut für Humangenetik · Technical University of Munich

   Affiliation as printed

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

2. Heike Kölbel

   Essen University Hospital · University of Duisburg-Essen

   Affiliation as printed

   Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Duisburg-Essen University , Essen 45147 ,

   Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Duisburg-Essen University, Essen 45147, Germany

3. Philip Harrer

   Helmholtz Munich · Institut für Humangenetik · Technical University of Munich

   Affiliation as printed

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

   Institute of Neurogenomics , Helmholtz Zentrum Munich, Neuherberg 85764 ,

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

   Institute of Neurogenomics, Helmholtz Munich, Neuherberg 85764, Germany

4. Robert Kopajtich

   Helmholtz Munich · Institut für Humangenetik · Technical University of Munich

   Affiliation as printed

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

   Institute of Neurogenomics , Helmholtz Zentrum Munich, Neuherberg 85764 ,

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

   Institute of Neurogenomics, Helmholtz Munich, Neuherberg 85764, Germany

5. Pinki Munot

   Great Ormond Street Hospital

   Affiliation as printed

   Dubowitz Neuromuscular Centre, Great Ormond Street Hospital , London WC1N 3JH ,

   Dubowitz Neuromuscular Centre, Great Ormond Street Hospital , London WC1N 3JH  

6. Melanie T. Achleitner

   Paracelsus Medical University · Salzburger Landeskliniken

   Affiliation as printed

   University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU) , Salzburg 5020 ,

   University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria

7. Susann Badmann

   Institut für Humangenetik · Technical University of Munich

   Affiliation as printed

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

8. Melanie Brügger

   Institut für Humangenetik · Technical University of Munich

   Affiliation as printed

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

9. Theresa Brunet

   Institut für Humangenetik · Technical University of Munich

   Affiliation as printed

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

   Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

10. Gisèle Bonne

    Inserm · Sorbonne Université · Institut de Myologie · Centre de Recherche en Myologie

    Affiliation as printed

    Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie , Paris 75013 ,

    Sorbonne Université, Inserm, Institut de Myologie, Centre de recherche en Myologie , Paris 75013 ,

11. Laura Ebner

    Paracelsus Medical University · Salzburger Landeskliniken

    Affiliation as printed

    University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU) , Salzburg 5020 ,

    University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria

12. Peyman Eshraghi

    Mashhad University of Medical Sciences

    Affiliation as printed

    Clinical Research Development Unit of Akbar Hospital, Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad 9177949025 ,

    Clinical Research Development Unit of Akbar Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

13. Ahmad Shah Farhat

    Mashhad University of Medical Sciences

    Affiliation as printed

    Neonatal Research Center, Mashhad University of Medical Sciences , Mashhad 9177949025 ,

    Neonatal Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

14. René G. Feichtinger

    Paracelsus Medical University · Salzburger Landeskliniken

    Affiliation as printed

    University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU) , Salzburg 5020 ,

    University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria

15. Elisabeth Graf

    Institut für Humangenetik · Technical University of Munich

    Affiliation as printed

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

16. Anna Marcé‐Grau

    Vall d'Hebron Hospital Universitari

    Affiliation as printed

    Department of Pediatric Neurology, Vall D'Hebron University Hospital, Vall D'Hebron Hospital Campus , Barcelona 08035 ,

    Department of Pediatric Neurology, Vall d'Hebron University Hospital, Vall d'Hebron Hospital Campus , Barcelona 08035 ,

    Department of Pediatric Neurology, Vall d'Hebron University Hospital, Vall d'Hebron Hospital Campus, Barcelona 08035, Spain

17. Andreas Hahn

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Department of Child Neurology, Justus-Liebig-University Giessen , Giessen 35390 ,

    Department of Neonatology, Justus-Liebig-University Giessen , Giessen 35390 ,

    Departments of Neonatology and Child Neurology, Justus-Liebig-University Giessen, Giessen 35390, Germany

18. Henry Houlden

    UCL Queen Square Institute of Neurology · University College London

    Affiliation as printed

    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London WC1N 3BG ,

    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK

19. Ehsan Ghayoor Karimiani

    UCL Queen Square Institute of Neurology · University College London

    Affiliation as printed

    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London WC1N 3BG ,

    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK

20. Véronique Manel

    Hôpital Femme Mère Enfant · Hospices Civils de Lyon

    Affiliation as printed

    Service de Médecine Physique et Réadaptation Pédiatrique, L'Escale, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Groupement Est , Bron 69500 ,

    Service de Médecine Physique et Réadaptation Pédiatrique, L'Escale, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Groupement Est , 69500 Bron ,

21. Katharina Mayerhanser

    Institut für Humangenetik · Technical University of Munich

    Affiliation as printed

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

22. Juliette Nectoux

    Hôpital Femme Mère Enfant · Hospices Civils de Lyon

    Affiliation as printed

    Service de Médecine Physique et Réadaptation Pédiatrique, L'Escale, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Groupement Est , Bron 69500 ,

    Service de Médecine Physique et Réadaptation Pédiatrique, L'Escale, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Groupement Est , 69500 Bron ,

23. Isabelle P. Nelson

    Inserm · Sorbonne Université · Institut de Myologie · Centre de Recherche en Myologie

    Affiliation as printed

    Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie , Paris 75013 ,

    Sorbonne Université, Inserm, Institut de Myologie, Centre de recherche en Myologie , Paris 75013 ,

24. Rahul Phadke

    Great Ormond Street Hospital

    Affiliation as printed

    Dubowitz Neuromuscular Centre, Great Ormond Street Hospital , London WC1N 3JH ,

    Dubowitz Neuromuscular Centre, Great Ormond Street Hospital , London WC1N 3JH  

25. Holger Prokisch

    Helmholtz Munich · Institut für Humangenetik · Technical University of Munich

    Affiliation as printed

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

    Institute of Neurogenomics , Helmholtz Zentrum Munich, Neuherberg 85764 ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

    Institute of Neurogenomics, Helmholtz Munich, Neuherberg 85764, Germany

26. Saeid Sadeghian

    Ahvaz Jundishapur University of Medical Sciences

    Affiliation as printed

    Department of Pediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences , Ahvaz 6135715753 ,

    Department of Pediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715753, Iran

27. Alice Saparov

    Helmholtz Munich · Institut für Humangenetik · Technical University of Munich

    Affiliation as printed

    Helmholtz Association, Munich School for Data Science (MUDS) , Helmholtz Zentrum Munich, Munich 85764 ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

    Institute of Neurogenomics , Helmholtz Zentrum Munich, Neuherberg 85764 ,

    Helmholtz Association—Munich School for Data Science (MUDS) , Munich ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

    Institute of Neurogenomics, Helmholtz Munich, Neuherberg 85764, Germany

28. Anne Schänzer

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Institute of Neuropathology, Justus Liebig University Giessen , Giessen 35392 ,

    Institute of Neuropathology, Justus Liebig University Giessen, Giessen 35392, Germany

29. Ulrike Schara

    Essen University Hospital · University of Duisburg-Essen

    Affiliation as printed

    Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Duisburg-Essen University , Essen 45147 ,

    Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Duisburg-Essen University, Essen 45147, Germany

30. Julia Katharina Schmidt

    Universitätsmedizin Göttingen · University of Göttingen

    Affiliation as printed

    Institute of Human Genetics, University Medical Center Göttingen , Göttingen 37073 ,

31. Rahel Schuler

    Justus-Liebig-Universität Gießen

    Affiliation as printed

    Department of Child Neurology, Justus-Liebig-University Giessen , Giessen 35390 ,

    Department of Neonatology, Justus-Liebig-University Giessen , Giessen 35390 ,

    Departments of Neonatology and Child Neurology, Justus-Liebig-University Giessen, Giessen 35390, Germany

32. Caroline A. Sewry

    Salford Royal NHS Foundation Trust · Robert Jones and Agnes Hunt Orthopaedic Hospital · Salford Royal Hospital · Robert Jones and Agnes Hunt Orthopaedic Hospital NHS Trust · Northern Care Alliance NHS Foundation Trust

    Affiliation as printed

    Cellular Pathology, Salford Royal Hospital NHS Foundation Trust, Northern Care Alliance , Manchester M6 8HD ,

    Wolfson Centre for Neuromuscular Disorders, Robert Jones and Agnes Hunt Orthopaedic Hospital , Oswestry SY10 7AG ,

    Cellular Pathology, Salford Royal Hospital NHS Foundation Trust, Northern Care Alliance, Manchester M6 8HD, UK

    Wolfson Centre for Neuromuscular Disorders, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry SY10 7AG, UK

33. Gholamreza Shariati

    Ahvaz Jundishapur University of Medical Sciences

    Affiliation as printed

    Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences , Ahvaz 6135715753 ,

    Narges Medical Genetics and Prenatal Diagnosis Laboratory , Kianpars, Ahvaz 61556-89467 ,

    Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715753, Iran

    Narges Medical Genetics and Prenatal Diagnosis Laboratory , Kianpars, Ahvaz ,

    Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran

34. Silke Slanz

    Institut für Humangenetik · Technical University of Munich

    Affiliation as printed

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

35. Dmitrii Smirnov

    Helmholtz Munich · Institut für Humangenetik · Technical University of Munich

    Affiliation as printed

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

    Institute of Neurogenomics , Helmholtz Zentrum Munich, Neuherberg 85764 ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

    Institute of Neurogenomics, Helmholtz Munich, Neuherberg 85764, Germany

36. Rivka Sukenik Halevy

    Tel Aviv University · Meir Medical Center

    Affiliation as printed

    Genetic Institute, Meir Medical Center , Kfar Saba 4428164 ,

    School of Medicine, Faculty of Medical and Health Sciences, Tel Aviv University , Tel Aviv 69978 ,

    Genetic Institute, Meir Medical Center, Kfar Saba 4428164, Israel

    School of Medicine, Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 69978, Israel

37. Homa Tajsharghi

    University of Skövde

    Affiliation as printed

    Division of Biomedicine, School of Health Sciences, University of Skovde , Skovde 541 28 ,

    Division of Biomedicine, School of Health Sciences, University of Skovde, Skovde 541 28, Sweden

38. Mehran Beiraghi Toosi

    Mashhad University of Medical Sciences

    Affiliation as printed

    Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences , Mashhad 9177949025 ,

    Neuroscience Research Center, Mashhad University of Medical Sciences , Mashhad 9177948564 ,

    Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran

39. Laura Trujillano

    Vall d'Hebron Institut de Recerca

    Affiliation as printed

    Clinical and Molecular Genetics Area, Vall D'Hebron Hospital Medicine Genetics Group, Vall D'Hebron Research Institute (VHIR) , Barcelona 08035 ,

    Clinical and Molecular Genetics Area, Vall d'Hebron Hospital Medicine Genetics Group, Vall d'Hebron Research Institute (VHIR), Barcelona 08035, Spain

40. Joachim Weis Aachen Institute of Neuropathology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Neuropathology, RWTH Aachen University Hospital , Aachen 52074 ,

    Institute of Neuropathology, RWTH Aachen University Hospital, Aachen 52074, Germany

41. Louise C. Wilson

    Great Ormond Street Hospital

    Affiliation as printed

    Department of Clinical Genetics, Great Ormond Street Hospital , London WC1N 3JH ,

    Department of Clinical Genetics, Great Ormond Street Hospital, London WC1N 3JH, UK

42. Rabah Ben Yaou

    Inserm · Sorbonne Université · Institut de Myologie · Centre de Recherche en Myologie

    Affiliation as printed

    Sorbonne Université, Inserm, Institut de Myologie, Centre de Recherche en Myologie , Paris 75013 ,

    Sorbonne Université, Inserm, Institut de Myologie, Centre de recherche en Myologie , Paris 75013 ,

43. Mina Zamani

    UCL Queen Square Institute of Neurology · University College London

    Affiliation as printed

    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London WC1N 3BG ,

    Narges Medical Genetics and Prenatal Diagnosis Laboratory , Kianpars, Ahvaz 61556-89467 ,

    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK

    Narges Medical Genetics and Prenatal Diagnosis Laboratory , Kianpars, Ahvaz ,

    Narges Medical Genetics and Prenatal Diagnosis Laboratory, Kianpars, Ahvaz, Iran

44. Jana Zschüntzsch

    Universitätsmedizin Göttingen · University of Göttingen

    Affiliation as printed

    Department of Neurology, University Medical Center , Göttingen 37075 ,

45. Uwe Kornak

    Universitätsmedizin Göttingen · University of Göttingen

    Affiliation as printed

    Institute of Human Genetics, University Medical Center Göttingen , Göttingen 37073 ,

46. David Gómez‐Andrés

    Vall d'Hebron Hospital Universitari

    Affiliation as printed

    Department of Pediatric Neurology, Vall D'Hebron University Hospital, Vall D'Hebron Hospital Campus , Barcelona 08035 ,

    Department of Pediatric Neurology, Vall d'Hebron University Hospital, Vall d'Hebron Hospital Campus , Barcelona 08035 ,

    Department of Pediatric Neurology, Vall d'Hebron University Hospital, Vall d'Hebron Hospital Campus, Barcelona 08035, Spain

47. Reza Maroofian

    UCL Queen Square Institute of Neurology · University College London

    Affiliation as printed

    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology , London WC1N 3BG ,

    Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK

48. Juliane Winkelmann

    Helmholtz Munich · Munich Cluster for Systems Neurology · Institut für Humangenetik · Technical University of Munich

    Affiliation as printed

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

    Institute of Neurogenomics , Helmholtz Zentrum Munich, Neuherberg 85764 ,

    Munich Cluster for Systems Neurology (SyNergy) , Munich 81377 ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

    Institute of Neurogenomics, Helmholtz Munich, Neuherberg 85764, Germany

    Munich Cluster for Systems Neurology (SyNergy), Munich 81377, Germany

49. Andreas Roos

    University of Ottawa · Children's Hospital of Eastern Ontario · Ottawa Hospital · Essen University Hospital · uOttawa Brain and Mind Research Institute · Heinrich Heine University Düsseldorf · University of Duisburg-Essen

    Affiliation as printed

    Department of Neurology, Heinrich Heine University Düsseldorf , Düsseldorf 40225 ,

    Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Duisburg-Essen University , Essen 45147 ,

    Division of Neurology, Department of Medicine, Children’s Hospital of Eastern Ontario Research Institute, the Ottawa Hospital, and Brain and Mind Research Institute, University of Ottawa , Ottawa , K1H 8L6

    Department of Neuropediatrics and Neuromuscular Centre for Children and Adolescents, Center for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Duisburg-Essen University, Essen 45147, Germany

    Division of Neurology, Department of Medicine, Children' s Hospital of Eastern Ontario Research Institute, The Ottawa Hospital, and Brain and Mind Research Institute, University of Ottawa , Ottawa K1H 8L6 ,

50. Johannes Adalbert Mayr

    Paracelsus Medical University · Salzburger Landeskliniken

    Affiliation as printed

    University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU) , Salzburg 5020 ,

    University Children's Hospital, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), 5020 Salzburg, Austria

51. Matias Wagner corresponding

    Helmholtz Munich · LMU Klinikum · Institut für Humangenetik · Technical University of Munich · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilian University (LMU) Munich , Munich 80337 ,

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich , Munich 81675 ,

    Institute of Neurogenomics , Helmholtz Zentrum Munich, Neuherberg 85764 ,

    Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilian University (LMU) Munich, Munich 80337, Germany

    Institute of Human Genetics, School of Medicine and Health, Technical University of Munich, Munich 81675, Germany

    Institute of Neurogenomics, Helmholtz Munich, Neuherberg 85764, Germany